In January 2014, the FDA approved the melatonin receptor agonist tasimelteon (Hetlioz) as the first treatment for non-24- hour sleep-wake disorder (“non-24”), a chronic circadian disorder that affects the timing of sleep, in individuals who are completely blind.
[1] Tasimelteon should be taken at the same time every night before bedtime, with limited activities after taking the drug.
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Approval was based on 2 studies of 104 totally blind patients with non-24 disorder in which tasimelteon treatment significantly increased nighttime sleep and decreased daytime sleep duration compared with placebo.
[1] The most common side effects with tasimelteon use were headache, elevated alanine aminotransferase levels in the blood, drowsiness, upper respiratory or urinary tract infection, nightmares/unusual dreams, and disturbed nighttime sleep.
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Signs and symptoms

Consider the following to determine the nature of the patient’s circadian rhythm disorder:

Duration of symptoms (transient vs chronic)

Pattern of the sleep-wake cycle: Allows diagnosis within chronic subtypes

Diagnosis

The diagnosis of circadian rhythm disorders is primarily based on a thorough history. In cases of sleeplessness, it is important to distinguish individuals with difficulty initiating sleep from those with difficulty maintaining sleep, those with significant daytime impairment, and those with nonrestorative sleep.

The physical examination is focused on identifying risk factors for other conditions that may precipitate, exacerbate, or mimic sleeplessness/insomnia (eg, depression, obstructive sleep apnea [OSA], neurodegenerative disease). Examination includes the following assessments:

General affect or sense of well-being in those with sleeplessness/insomnia as a primary sleep complaint

Management

Therapy for circadian rhythm disturbances is largely behavioral. However, the direction of evaluation and treatment plans is influenced by differentiating between transient and chronic circadian rhythm disorders as well as between primary and secondary disorders.

DSPS often resolves in adulthood. ASPS often responds well to a combination of behavioral and pharmacologic intervention.

Background

Disturbances in circadian rhythm—the approximately 24-hour cycles that are endogenously generated by an organism—can be categorized into 2 main groups: transient disorders and chronic disorders. Transient disorders include jet lag or a changed sleep schedule due to work, social responsibilities, or illness. (See Etiology, Prognosis, and Presentation.)

Circadian rhythm disorders - Malfunctions of the circadian timing system or the biologic clock

DSPS is characterized by a persistent inability (>6 mo) to fall asleep and awaken at socially accepted times. Once asleep, these patients are able to maintain their sleep and have normal total sleep times. In contrast, patients with insomnia have a lower than normal total sleep time due to difficulties in initiating or maintaining sleep. (See Etiology, Prognosis, Presentation, Workup, Treatment, and Medication.)

ASPS is characterized by persistent, early evening sleep onset (between 6:00 pm and 9:00 pm), with an early morning wake-up time, generally between 3:00 am and 5:00 am. ASPS is less common than DSPS; it most frequently occurs in elderly patients and in individuals who are depressed.

An irregular sleep-wake schedule features multiple sleep episodes without evidence of recognizable ultradian or circadian features of sleep and wakefulness. As with ASPS and DSPS, total sleep time is normal. Daily sleep logs demonstrate irregularity not only of sleep but also of daytime activities, including eating.

Physiology

The neural basis of the circadian rhythm, the suprachiasmatic nuclei (SCN), is located in the anterior ventral hypothalamus and has been identified as the substrate that generates circadian activity. SCN lesions produce loss of circadian rhythmicity of the sleep-wake cycle, the activity-rest cycle, skin temperature, and corticosteroid secretion. (See Etiology.)

Other pacemakers that are not located in the SCN are observed. For instance, core body temperature rhythm persists despite bilateral ablation of SCN. Furthermore, free-running studies have provided evidence for multiple circadian oscillators. Under free-running conditions, circadian rhythm may split into independent components.

Complications

The consequences of poor sleep are well established. They include irritability, impaired social interactions and psychomotor coordination, poor daytime performance, and daytime sleepiness. The literature supports the relationship of poor sleep to automobile accidents, heavy machinery accidents, and other catastrophes. (See Prognosis.)

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Etiology

Most of the time, the biologic clock or the circadian rhythm is in synchronization with the 24-hour day-night environment. However, in some individuals, the biologic circadian rhythm of sleep and wakefulness is out of phase with the conventional or desired sleep-wake schedule. Postulated reasons for that breakdown are as follows.

Sensitivity to zeitgebers

Sensitivity to zeitgebers (ie, environmental cues) may be altered or disrupted, which can be demonstrated under free-running conditions. Altered or disrupted sensitivity to zeitgebers is probably the most common cause of circadian rhythm disorder.

Disrupted pacemaker function

A dysfunction may be present in the internal coupling mechanisms of biologic pacemakers (eg, the coupling of the sleep-wake cycle with the temperature cycle).

Environment

Light, higher levels of noise, and elevated room temperature are not conducive to good sleep and are important variables to consider in shift and night workers

Travel

The severity of jet lag is related to the direction of travel (ie, more frequently seen when traveling in an eastward direction) and the number of time zones crossed. Most patients experience jet lag if they cross 3 or more time zones. The rate of adjustment is 1.5 hours per day after an eastward flight and 1 hour per day when the flight is in a westward direction.

Other factors that may affect the severity of jet lag are age, the ability to sleep while traveling, the time of the day at the destination, and exposure to light. Studies have even looked at cabin pressure and the slight oxygen deprivation experienced during flights as contributing factors to symptoms of jet lag.

Neurologic disease

Alzheimer disease is one of the more common examples of neurologic disease associated with circadian rhythm disturbance; however, irregular sleep-wake cycles also can be seen in other neurodegenerative diseases. The phenomenon of sundowning is best described in Alzheimer disease and is characterized by sleep disruptions with awakenings and confusion.

Circadian rhythm disturbances have been reported in children with cancer and may be seen following injury to the hypothalamus or brainstem in those with endocrine dysfunction or following cranial irradiation.
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In children with autism spectrum disorder, sleep onset and sleep maintenance insomnia have been described.
[4] They have also been associated with abnormal sleep-wake rhythms.

Shift work

Rapid shift changes and shift changes in the counterclockwise direction are most likely to cause symptoms.

Lifestyle

Lifestyle and social pressure (to stay up late) can exacerbate a circadian rhythm disorder.

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Epidemiology

Occurrence in the United States

Delayed sleep-phase syndrome (DSPS) is common. Approximately 7-10% of patients who complain of insomnia are diagnosed with a circadian rhythm disorder, most often DSPS. The prevalence of DSPS is probably higher than that, because the total sleep time is typically normal in patients with DSPS and because patients with DSPS adjust their lifestyle to accommodate their sleep schedule and do not seek medical treatment. In adolescence, the prevalence is approximately 7%.

True advanced sleep-phase syndrome (ASPS) is probably quite rare. However, an age-related phase advance is common in elderly patients because they tend to go to sleep early and get up early.

The prevalence of irregular sleep-wake schedules has not been established but is said to be quite high. An irregular sleep-wake schedule is common in patients with Alzheimer disease.

Approximately 20% of US workers perform shift work, but not all of these workers develop shift-work syndrome, and individual phase tolerance is observed.

International occurrence

Dagan et al reported the characteristics of 322 Israeli patients with circadian rhythm sleep disorder and found that most of these patients (83.5%) had DSPS. About 90% of the patients with DSPS reported onset of the syndrome in early childhood or adolescence.
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A cross-sectional, nationwide epidemiologic study in Norway established an overall prevalence of DSPS of 0.17% when strict International Classification of Sleep Disorders (ICSD) criteria were used.
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Race-related demographics

Race has been associated with variations in incidence of obstructive sleep apnea (OSA); however, many variables may be associated with these differences, and further research is necessary to evaluate this.

Sex-related demographics

The sex difference in circadian rhythm disorders seems to be age related. In children and adolescents, no significant prevalence based on sex is observed. Moreover, little to no difference in prevalence based on sex is observed in patients aged 20-40 years. In persons older than 40 years, however, women are 1.3 times more likely than men to report insomnia.

Age-related demographics

Circadian rhythm cycles undergo changes during puberty, as do other physiologic systems. At this time, increased daytime sleepiness is seen along with the development of sleep-phase delay. Early school start times at this critically important developmental phase, coupled with afterschool activities and homework, are associated with sleep deprivation and phase shifting in children and adolescents. This can lead to symptoms of daytime sleepiness, poor concentration, and impaired performance.

DSPS is the most common circadian rhythm disorder in children and adolescents. ASPS is more likely to appear in elderly individuals. Health risks associated with shift work, such as gastrointestinal (GI) and psychosomatic symptoms, increase with age.

Irregular sleep-wake rhythms can be seen in patients with neurologic impairment, including those with dementia.

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Prognosis

Prognoses in circadian rhythm disorders include the following:

Jet lag - This is a transient condition that has a good prognosis

Shift work - Abrupt changes in schedule and counterclockwise shifts are associated with daytime sleepiness and impaired performance; older patients may not adjust well to shift work

Delayed sleep-phase syndrome (DSPS) - This is typically seen in adolescents and young adults; this sleep pattern often resolves in adulthood

Advanced sleep-phase syndrome (ASPS) - This is prominent in the elderly and often responds well to a combination of behavioral and pharmacologic intervention

Other conditions - Children with special needs, including attention deficit hyperactivity disorder and developmental disabilities, generally respond well to behavioral intervention

Morbidity and mortality

The mortality rates associated with circadian rhythms are difficult to assess. Many deaths related to circadian rhythm disorders are the result of impaired performance secondary to sleep deprivation; therefore, many times, the deaths are categorized into different headings (eg, motor vehicle accidents, heavy machinery accidents). Sometimes, deaths are sequelae of the use of hypnotics, alcohol, or both to treat insomnia.

Shift workers have been found to have a 40% greater cardiovascular disease risk than nonshift workers. The frequency of GI, psychosomatic, and psychiatric symptoms is also increased in shift workers. In addition, increased alcohol and drug use, as well as emotional problems, have been described.

Daytime sleepiness in students with DSPS has been correlated with negative mood and increased smoking and alcohol consumption.

Some of the features of depressive disorders, such as early morning awakening and decreased rapid eye movement (REM) latency, are suggestive of ASPS. Whether these changes are secondary to depression or actually cause it has not been established.

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Patient Education

Education can play a critical role in therapeutic response; however, education in sleep hygiene without other interventions is often insufficient.

Patients should be advised of risks secondary to sleepiness and have follow-ups after treatment to determine if risk factors have been satisfactorily addressed.